CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors.

Schulz, David W.; Mansbach, Robert S.; Sprouse, Jeffrey; Braselton, John P.; Collins, J.L.; Corman, Michael L.; Dunaiskis, Audrey; Faraci, Steve; Schmidt, Anne W.; Seeger, Thomas; Seymour, Patricia A.; Tingley, F. David; Winston, Elizabeth; Chen, Y L; Heym, James

doi:10.1073/pnas.93.19.10477

Cited by 348 publications

(227 citation statements)

References 39 publications

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“…While there is the possibility that this compound may also affect other ) during each of the four 15-min self-administration bins on infusions self-administered by rats trained to self-administer 0.5 mg/ kg/infusion cocaine. The number of infusions delivered during extinction was significantly less than baseline in the second, binding sites, its selectivity and specificity for the CRH1 receptor make this possibility unlikely (Schulz et al 1996;McCarthy et al 1999). Cocaine-reinforced responding was decreased across several doses of cocaine, with the dose-response curve for cocaine self-administration shifted downward and flattened (Figure 2), suggesting that CP-154,526 was decreasing cocaine reinforcement.…”

Section: Discussionmentioning

confidence: 99%

“…CP-154,526 binds with a high affinity (Ki Ͻ 10 nM) to the CRH1 receptor subtype (Schulz et al 1996), suggesting that the effects of the compound on cocaine self-administration resulted primarily from interactions at this receptor site. While there is the possibility that this compound may also affect other Role for CRH in the Effects of Cocaine 583 binding sites, its selectivity and specificity for the CRH1 receptor make this possibility unlikely (Schulz et al 1996;McCarthy et al 1999). Cocaine-reinforced responding was decreased across several doses of cocaine, with the dose-response curve for cocaine self-administration shifted downward and flattened (Figure 2), suggesting that CP-154,526 was decreasing cocaine reinforcement.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…The following experiments were therefore designed to determine the effects of pretreatment with CP-154,526, a centrally active, small molecule CRH1 receptor subtype antagonist (Mansbach et al 1997), on intravenous cocaine self-administration in rats. This compound was selected for study in these experiments because, unlike peptide antagonists such as D -Phe CRF 12-41 , CP-154,526 enters the brain following systemic administration (Schulz et al 1996;McCarthy et al 1999), which makes it a potentially more useful tool for investigating the effects of CRH in cocaine reinforcement. In fact, this compound has recently been reported to attenuate the electric footshock-induced reinstatement of cocaine-and heroinseeking behavior , suggesting the involvement of CRH in the relapse to drug seeking.…”

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Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Goeders

Guerin

2000

Neuropsychopharmacology

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The role for corticotropin-releasing hormone (CRH) receptors in the maintenance of intravenous cocaine self-administration in rats was investigated using the centrally active, small molecule CRH1 receptor antagonist 526. In these experiments, adult male Wistar rats were allowed alternating 15-min periods of access to food reinforcement and cocaine selfadministration (0.125, 0.25 Self-administration; Rat During the past several years, research from our laboratory has focused on the potential involvement of the hypothalamic-pituitary-adrenal (HPA) axis in cocaine reinforcement. The HPA axis consists of a complex, well-regulated interaction between the brain, the anterior pituitary gland, and the adrenal cortex. The initial step in the activation of the HPA axis is the neuronally regulated secretion of the peptide corticotropin-releasing hormone (CRH) from the parvocellular division of the paraventricular nucleus (PVN) of the hypothalamus. CRH is released by the hypothalamus into the adenohypophyseal portal circulation to act on the pituitary to induce the secretion of adrenocorticotropin hormone (ACTH). ACTH diffuses through the general circulation until it reaches the adrenal glands. There it stimulates the biosynthesis of adrenocorticosteroids, most notably the glucocorticoids, cortisol (in humans) and corticosterone (in rats), which results in their secretion from the adrenal cortex.Cocaine has been reported to stimulate HPA axis activity in a manner analogous to various stressors, which indicates that this system has the potential to influence many of the neurochemical and behavioral effects of the drug. For example, the acute administration of cocaine dose-dependently increases plasma concentrations of corticosterone, ACTH, and ␤ -endorphin in rats (Moldow and Fischman 1987;Rivier and Vale 1987;Borowsky and Kuhn 1991). Cocaine also stimulates the release of ACTH and cortisol in humans (Mendelson et al. 1989;Baumann et al. 1995) and non-human primates (Sarnyai et al. 1996) by increasing the peak amplitude of secretory pulses of these hormones without altering pulse frequency, suggesting that these increases are driven by hypothalamic CRH (Mendelson et al. 1989;Teoh et al. 1994;Sarnyai et al. 1996). Cocaine-induced increases in ACTH and corticosterone in rats can be blocked by pretreatment with the CRH antagonist ␣ -helical CRF 9-41 (Sarnyai et al. 1992a), by immunoneutralization of CRH with an anti-CRH antibody (Rivier and Vale 1987;Sarnyai et al. 1992a), or by bilateral electrolytic lesions of the PVN (Rivier and Lee 1994), indicating that these increases are also mediated by the cocaine-induced release of CRH from parvocellular neurons in the PVN. Accordingly, it has been reported that cocaine administration also results in increases in hypothalamic CRH mRNA (Zhou et al. 1996;Rivier and Lee 1994) and alters CRH receptor binding measured autoradiographically in various regions of the rat brain (Goeders et al. 1990). These data suggest that the complex relationship between cocaine reinforcement and cort...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Goeders

Guerin

2000

Neuropsychopharmacology

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“…Secondly, in order to further characterize the e ects of CRH in both cell lines, we studied (1) the expression of CRH-R1 and -R2; and (2) the e ects of the selective CRH-R1 antagonist CP 154,526 (Schulz et al, 1996), as well as the selective CRH-R2 antagonist anti-Svg-30 (Ruhmann et al, 1998) upon CRH-mediated nitrite release.…”

Section: Introductionmentioning

confidence: 99%

Divergent effects of corticotropin releasing hormone on endothelial cell nitric oxide synthase are associated with different expression of CRH type 1 and 2 receptors

Cantarella

Lempereur

Lombardo

et al. 2001

British J Pharmacology

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1 Endothelium is a target for an array of factors involved in in¯ammation. Endothelial cells express receptors for CRH, a neuropeptide produced during in¯ammation. We report both the concentration-dependent inhibitory e ect of CRH upon cytokine-stimulated nitrite release by H5V murine endothelioma cells, and its stimulatory one in HUVEC cells. 2 Western blot analysis showed that CRH inhibits cytokine-stimulated iNOS protein in H5V cells, and, instead, potentiated it in HUVEC cells. 3 H5V cells expressed both CRH receptors (CRH-R1 and R2) mRNAs, whereas HUVEC cells expressed the CRH-R2 mRNA solely. 4 CRH increased medium nitrites and iNOS protein expression in H5V cells pretreated with the selective CRH-R1 antagonist CP 154,526. However, the selective CRH-R2 antagonist anti-Svg-30 failed to produce similar e ects. In fact, anti-Svg-30 inhibited CRH-induced increase of nitrite release and iNOS expression in HUVEC cells. 5 Our results con®rm the activating role of CRH on endothelial cells, although it suggests its possible inhibitory role in the late phase of the in¯ammatory response. NO-mediated e ects of CRH on endothelial cells could be exploited in therapeutic strategies related to in¯ammatory and/or degenerative diseases.

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Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain

et al. 1999

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Two different corticotropin‐releasing factor (CRF) receptors, CRF1 and CRF2, have been identified in rat and human brain. Although the two receptor subtypes show a markedly different distribution in the rat brain, their distribution in the primate brain has not been described previously. In this study, the neuroanatomic distribution of CRF1 and CRF2 receptor binding sites in rhesus monkey (Macaca mulatta) was assessed by using iodine 125 ([125I)‐Tyr0]‐sauvagine with or without the selective CRF1 receptor antagonist CP‐154,526–1. Radiolabeled human cRNA probes were used to map the distribution of the two receptor mRNAs with in situ hybridization. Both CRF1 and CRF2 receptors were found in the pituitary and throughout the neocortex (especially, in prefrontal, cingulate, striate, and insular cortices), amygdala, and hippocampal formation of the monkey brain. This is in contrast to the distribution of these receptors reported in the rat brain, in which generally only the CRF1 receptor is found in the pituitary and neocortex. These results suggest that, in primates, both CRF1 and CRF2 receptors may be involved in mediating the effects of CRF on cognition, behavior, and pituitary‐adrenal function. The presence of CRF1 (but not CRF2) receptors within the locus coeruleus, cerebellar cortex, nucleus of the solitary tract, thalamus, and striatum and of CRF2 (but not CRF1) receptors in the choroid plexus, certain hypothalamic nuclei, the nucleus prepositus, and the nucleus of the stria terminalis suggests that each receptor subtype also may have distinct functional roles within the primate central nervous system. J. Comp. Neurol. 408:365–377, 1999. © 1999 Wiley‐Liss, Inc.

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CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors.

Cited by 348 publications

References 39 publications

Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

Divergent effects of corticotropin releasing hormone on endothelial cell nitric oxide synthase are associated with different expression of CRH type 1 and 2 receptors

Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain

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